Karen M. Daly

Cyclophosphamide, vincristine, methotrexate with leucovorin rescue, and cytarabine (COMLA) combination sequential chemotherapy for advanced diffuse histiocytic lymphoma.

A program of combination sequential chemotherapy using cyclophosphamide, vincristine, methotrexate with leucovorin rescue, and cytarabine (COMLA) was administered to 42 previously untreated patients with advanced diffuse histiocytic lymphoma. Twenty-three patients achieved a complete remission as determined by strict clinical restaging criteria. The observed median duration of survival for the complete responders is longer than 33 months. Eight patients achieved a partial response, with a median survival longer than 21 months. Eleven patients showed no response, with a median survival of 5 months. Toxicity was acceptable. None of the responders have shown central nervous system relapse. There was no difference in response rates between patients with stage III or IV lymphoma or between asymptomatic or symptomatic patients. The COMLA program produces a high rate of complete and durable remissions and should be considered as an initial form of management of patients with advanced diffuse histiocytic lymphoma.

Relapse after interferon alfa-2b therapy for hairy-cell leukemia: analysis of prognostic variables.

Sixty-nine patients with hairy-cell leukemia (HCL) were treated with interferon alfa-2b (IFN) in a single-institution study. The dose used was 2 x 10(6) U/m2 self-administered subcutaneously three times weekly, for a planned treatment duration of 12 to 18 months. Of the 68 evaluable patients, the major response rate was 75%, with 13% complete responses (CRs) and 62% partial responses (PRs). An additional eleven patients (16%) had minor responses (MRs). Duration of response was denoted as failure-free survival (FFS), defined as the time from the end of IFN therapy to a need for further antileukemic therapy. Of the 60 responding patients followed after discontinuation of IFN, 27 have relapsed, requiring further therapy. The median actuarial FFS for these 60 patients is 25.4 months. All but five patients are alive, and the actuarial overall survival for the 69 patients is 91% +/- 4% at 4 years from the start of IFN. The best indicators of relapse were the neutrophil alkaline phosphatase (NAP) score and degree of residual bone marrow hairy cells (%HCL) at the completion of therapy. Patients with NAP less than 30 (n = 21) had the best prognosis (median FFS, 30.4 months), while those with NAP greater than or equal to 30 and %HCL less than or equal to 30 (n = 21) or %HCL greater than 30 (n = 16) had intermediate and poor prognoses, respectively (median FFS, 23.5 and 12.4 months) (P = .0005). Fourteen of the relapsing patients are evaluable for response to a second course of IFN, with seven PRs and four MRs. Stratified randomized trials are indicated to determine the role of maintenance therapy for responding patients.

A clinical and pharmacokinetic study of mitoxantrone in acute nonlymphocytic leukemia.

Twenty-two patients with relapsed or refractory acute leukemia received 31 treatment courses of mitoxantrone (10 to 12 mg/m2/d) as a one-hour infusion for five days. Seven of the 13 patients who had greater than or equal to 95% reduction in the leukemia cell mass, calculated using the bone marrow examination on day 6, achieved a complete remission (CR). These remissions lasted up to 14 months without additional therapy. There were no CRs among the 18 patients who had less than 95% cytoreduction by day 6. The sequential addition of 5-azacytidine (200 mg/m2/d) for three days in those patients with residual disease on day 6 provided little additional benefit. Nonhematological toxicity from mitoxantrone was mild, although fever and infection were common. A new high-performance liquid chromatography (HPLC) assay was used to describe the clinical pharmacokinetics of mitoxantrone. Neither clinical response nor toxicity was strongly correlated with the peak plasma mitoxantrone concentration on the first day (mean +/- SD, 510 +/- 206 ng/mL), nor the area under the concentration-time curve (484 +/- 229 ng X h/mL), nor the systemic clearance (405 +/- 124 mL/min/m2). Mitoxantrone causes rapid cytoreduction in acute nonlymphocytic leukemia (ANLL), but the optimal dose and schedule remain to be determined.

High-performance liquid chromatographic assay for mitoxantrone in plasma using electrochemical detection

A sensitive and specific high-performance liquid chromatographic (HPLC) assay was developed for the quantitation of mitoxantrone in plasma using electrochemical detection. Bisantrene was chosen as the internal standard. A reversed-phase, 10-microns muBondapak C18 analytical column (30 cm X 3.9 mm) with an isocratic mobile phase of 28% acetonitrile in 80 mM sodium formate buffer (pH 3.0) was used. The eluent was monitored by both electrochemical detection at an applied potential of +0.75 V vs. Ag/AgCl and visible absorbance at 660 nm. Only electrochemical detection was able to quantitate the internal standard and provided ten times higher sensitivity than visible absorbance for mitoxantrone with a detection limit as low as 0.1 ng/ml. Calibration curves in the range 0.1-1000 ng/ml showed good linearity (r = 0.998) and precision (coefficient of variation less than 10%). This HPLC method utilized a reproducible and inexpensive liquid-liquid extraction procedure. Using methylene chloride, the extraction efficacy of mitoxantrone from plasma was 85.3% with a coefficient of variation less than 2.1%. This new assay was then applied to measure mitoxantrone concentrations in plasma obtained from two leukemic patients receiving 12 mg/m2 mitoxantrone as a 1-h infusion.

Acute myeloid leukaemia following interferon-alfa treatment of hairy cell leukaemia.

Interferon-alfa (IFNa) has been used for the treatment of hairy cell leukaemia (HCL) since 1984 (Quesada et al, 1984). Late complications of IFNa therapy, such as second malignancies, have not been reported. We describe here a patient with HCL who developed acute myeloid leukaemia (AML) 6.5 years after initiation of IFNa therapy. Many features of this case are similar to those reported in therapy-related AML (t-AML) that follows alkylating agent therapy. A 5 7-year-old man with pancytopenia, splenomegaly and no history of chemical exposure was first seen in January 1984. A bone marrow specimen revealed HCL cells which exhibited tartrate-resistant acid phosphatase positivity. The patient underwent splenectomy with recovery of his blood counts. Three months later he was readmitted with fever: Mycobacterium kansasii was cultured from a mediastinal lymph node. He was treated with isoniazid, rifampin and ethambutol for 2 years. In February 1985 he became neutropenic and was started on IFNa-2b (1 x lo6 units/mz

Flow cytometry in hairy cell leukemia before and during interferon alfa‐2b therapy

Mononuclear cells from 15 patients with hairy cell leukemia were studied before and during therapy with interferon alfa‐2b (IFN) by regular peripheral blood differential counts and flow cytometry, using a panel of monoclonal antibodies (Moab). Seven leukemic phase patients (Group 1) had a mean leukocyte count of 48,870/μl at entry with a mean absolute hairy cell (HC) count of 40,100/μl. After 3 months on IFN, both parameters decreased significantly (WBC 3,500/μl; HC count 130/μl). In eight patients with a cytopenic form of the disease (Group 2) the mean leukocyte count rose from 2950/μl to 3890/μl while the mean absolute HC count decreased from 300/μl to 120/μl. The morphologic shifts correlated well with changes in the Moab reaction pattern. In Group 1 the activity of all Moab decreased significantly. In Group 2, only cells expressing Leu 3a and Leu 11a (a marker of natural killer cells) showed a significant shift, the latter increasing from 170/μl to 360/μl. This increase in natural killer cell antigen expression was not obvious based on routine morphologic observations alone. We show that flow cytometry may be a useful adjunct in monitoring the response of HCL to therapy. Changes in populations of cells that may be difficult to discriminate on morphologic grounds alone may be observed.